syndrome of inappropriate antidiuretic hormone secretion siadh

4/28/13 Syndrome of Inappropriate Antidiuretic Hormone Secretion

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Practice Essentials

The syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) is defined by the hyponatremia andhypo-osmolality resulting from inappropriate, continued secretion or action of the hormone despite normal orincreased plasma volume, which results in impaired water excretion. The key to understanding thepathophysiology, signs, symptoms, and treatment of SIADH is the awareness that the hyponatremia is a result ofan excess of water rather than a deficiency of sodium.

Essential update: Response to conivaptan of neurosurgical ICU patients with SIADH

A retrospective study involving 32 hyponatremic neurosurgical patients with SIADH examined the natremic

response to a single 20-mg bolus dose of conivaptan over a period of 48 hours.[1] From a baseline of 129.8 3.4mEq/L, the serum sodium concentration increased to 133.1 3.2 mEq/L by 6 hours after administration ofconivaptan and to 134.2 3.2 mEq/L by 24 hours, indicating a significant 24-hour natremic response. Patientswho failed to reach the primary end point (serum sodium increase 4 mEq/L over the first 24 hours) were treatedwith additional doses of conivaptan and other agents. On the basis of these findings, the authors recommend asingle 20-mg dose of conivaptan as the preferred initial approach to treating patients in the neurosurgical intensivecare unit who have SIADH, with the 24-hour natremic response dictating whether additional conivaptan doses or

other interventions are required.[1]

Signs and symptoms

Depending on the magnitude and rate of development, hyponatremia may or may not cause symptoms. Thehistory should take into account the following considerations:

In general, slowly progressive hyponatremia is associated with fewer symptoms than is a rapid drop ofserum sodium to the same valueSigns and symptoms of acute hyponatremia do not precisely correlate with the severity or the acuity of thehyponatremiaPatients may have symptoms that suggest increased secretion of ADH, such as chronic pain, symptomsfrom central nervous system or pulmonary tumors or head injury, or drug useSources of excessive fluid intake should be evaluatedThe chronicity of the condition should be considered

After the identification of hyponatremia, the approach to the patient depends on the clinically assessed volumestatus. Prominent physical findings may be seen only in severe or rapid-onset hyponatremia and can include thefollowing:

Confusion, disorientation, deliriumGeneralized muscle weakness, myoclonus, tremor, asterixis, hyporeflexia, ataxia, dysarthria, Cheyne-

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Stokes respiration, pathologic reflexesGeneralized seizures, coma

See Clinical Presentation for more detail.

Diagnosis

In the absence of a single laboratory test to confirm the diagnosis, SIADH is best defined by the classic Bartter-

Schwartz criteria, which can be summarized as follows[2] :

Hyponatremia with corresponding hypo-osmolalityContinued renal excretion of sodiumUrine less than maximally diluteAbsence of clinical evidence of volume depletionAbsence of other causes of hyponatremiaCorrection of hyponatremia by fluid restriction

The following laboratory tests may be helpful in the diagnosis of SIADH:

Serum sodium, potassium, chloride, and bicarbonatePlasma osmolalitySerum creatinineBlood urea nitrogenBlood glucoseUrine osmolalitySerum uric acidSerum cortisolThyroid-stimulating hormone

The patients volume should be assessed clinically to help rule out the presence of hypovolemia.

Imaging studies that may be considered include the following:

Chest radiography (for detection of an underlying pulmonary cause of SIADH)Computed tomography or magnetic resonance imaging of the head (for detection of cerebral edemaoccurring as a complication of SIADH, for identification of a CNS disorder responsible for SIADH, or forhelping to rule out other potential causes of a change in neurologic status)

See Workup for more detail.

Management

Treatment of SIADH and the rapidity of correction of hyponatremia depend on the following:

Degree of hyponatremiaWhether the patient is symptomaticWhether the syndrome is acute (< 48 hours) or chronicUrine osmolality and creatinine clearance

If the duration of hyponatremia is unknown and the patient is asymptomatic, it is reasonable to presume chronicSIADH. Diagnosis and treatment of the underlying cause of SIADH are also important.

In an emergency setting, aggressive treatment of hyponatremia should always be weighed against the risk ofinducing central pontine myelinolysis (CMP). Such treatment is warranted as follows:

Indicated in patients who have severe symptoms (eg, seizures, stupor, coma, and respiratory arrest),regardless of the degree of hyponatremiaStrongly considered for those who have moderate-to-severe hyponatremia with a documented duration ofless than 48 hours



The goal is to correct hyponatremia at a rate that does not cause neurologic complications, as follows:

Raise serum sodium by 0.5-1 mEq/hr, and not more than 10-12 mEq in the first 24 hoursAim at maximum serum sodium of 125-130 mEq/L

In an acute setting (< 48 hours since onset) where moderate symptoms are noted, treatment options forhyponatremia include the following:

3% hypertonic saline (513 mEq/L)Loop diuretics with salineVasopressin-2 receptor antagonists (aquaretics, such as conivaptan)Water restriction

In a chronic asymptomatic setting, the principal options are as follows:

Fluid restrictionVassopressin-2 receptor antagonistsIf vasopressin-2 receptor antagonists are unavailable or if local experience with them is limited, other agentsto be considered include loop diuretics with increased salt intake, urea, mannitol, and demeclocycline

See Treatment and Medication for more detail.

Background

The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is the most common cause of euvolemichyponatremia in hospitalized patients. The syndrome is defined by the hyponatremia and hypo-osmolality thatresults from inappropriate, continued secretion and/or action of antidiuretic hormone (ADH) despite normal orincreased plasma volume, which results in impaired water excretion. The antidiuretic hormone (ADH) promotes thereabsorption of water from the tubular fluid in the collecting duct, the hydro-osmotic effect, and it does not exert a

significant effect on the rate of Na+ reabsorption. A second action of ADH is to cause arteriolar vasoconstrictionand a rise in arterial blood pressure, the pressor effect.

Physiology of ADH

Arginine vasopressin (AVP), the naturally occurring ADH in humans, is an octapeptide similar in structure tooxytocin. AVP is synthesized in the cell bodies of neurons in the supraoptic and paraventricular nuclei of theanterior hypothalamus and travels along the supraopticohypophyseal tract into the posterior pituitary. Here, it isstored in secretory granules in association with a carrier protein, neurophysin, in the terminal dilatations ofsecretory neurons that rest against blood vessels.

The major stimuli for AVP secretion are hyperosmolality and effective circulating volume depletion, which aresensed by osmoreceptors and baroreceptors, respectively. Osmoreceptors are specialized cells in thehypothalamus that perceive changes in the extracellular fluid (ECF) osmolality. Baroreceptors are located in thecarotid sinus, aortic arch, and left atrium; these receptors participate in the nonosmolar control of AVP release byresponding to a change in effective circulating volume.

Three known receptors bind AVP at the cell membrane of target tissues: V1a, V1b (also known as V3), and V2;these mediate AVPs various effects.

V1a receptor is the vascular smooth muscle cell receptor but is also found on a number of other cells, such ashepatocytes, cardiac myocytes, platelets, brain, and testis. The V1a receptors signal by activation ofphospholipase C and elevation in intracellular calcium, which, in turn, stimulates vasoconstriction. V1b (V3)receptors are found predominantly in the anterior pituitary, where they stimulate ACTH secretion.

V2 receptors are coupled to adenylate cyclase, causing a rise in intracellular cyclic adenosine monophosphate(cAMP), which serves as the second messenger. V2 receptors are found predominantly on the basolateral

membrane of the principal cells of the connecting tubule and collecting duct of the distal nephron.[3] Activation ofthe V2 receptor results in insertion of the water channel aquaporin-2 in the luminal membrane of the collecting



duct, thus making it more permeable to water. Activation of the V2 receptors also increases urea and Na+ chloridereabsorption by the ascending limb of loop of Henle, thus increasing medullary tonicity and providing the osmotic

gradient for maximal water absorption.[3] V2 receptors are also found in vascular endothelial cells and stimulate the

release of von Willebrand factor.[3]

Normally, AVP secretion ceases when plasma osmolality falls below 275 mOsm/kg. This decrease causesincreased water excretion, which leads to a dilute urine with an osmolality of 40-100 mOsm/kg. When plasmaosmolality rises, AVP is secreted, which results in an increase in water reabsorption and an increase in urineosmolality to as much as 1400 mOsm/kg. An 8-10% reduction in circulating volume also significantly increasesAVP release. In most physiologic states, the volume receptors and osmoreceptors act in concert to increase ordecrease AVP release. However, a reduction in actual or effective circulating volume is an overriding stimulus forsecretion of AVP and takes precedence over extracellular osmolality when osmolality is normal or reduced.Finally, AVP is also released in response to stressful stimuli, such as pain or anxiety, and by various drugs. Thereleased AVP is rapidly metabolized in the liver and kidneys and has a half-life of 15-20 minutes.

Pathophysiology

The key to understanding the pathophysiology, signs, symptoms, and treatment of SIADH is the awareness that

the hyponatremia in this syndrome is a result of an excess of water and not a deficiency of Na+.

SIADH consists of hyponatremia, inappropriately elevated urine osmolality (>100 mOsm/kg), and decreasedserum osmolality in a euvolemic patient. SIADH should be diagnosed when these findings occur in the setting ofotherwise normal cardiac, renal, adrenal, hepatic, and thyroid function; in the absence of diuretic therapy; and inabsence of other factors known to stimulate ADH secretion, such as hypotension, severe pain, nausea, andstress.

In general, the plasma Na+ concentration is the primary osmotic determinant of AVP release. In persons withSIADH, the nonphysiological secretion of AVP results in enhanced water reabsorption, leading to dilutionalhyponatremia. While a large fraction of this water is intracellular, the extracellular fraction causes volumeexpansion. Volume receptors are activated and natriuretic peptides are secreted, which causes natriuresis andsome degree of accompanying potassium excretion (kaliuresis). Eventually, a steady state is reached and the

amount of Na+ excreted in the urine matches Na intake. Ingestion of water is an essential prerequisite to thedevelopment of the syndrome; regardless of cause, hyponatremia does not occur if water intake is severelyrestricted.

In addition to the inappropriate AVP secretion, persons with this syndrome may also have an inappropriate thirstsensation, which leads to an intake of water that is in excess of free water excreted. This increase in wateringested may contribute to the maintenance of hyponatremia.

Neurologic manifestations

Neurologic complications in SIADH occur as a result of the brain's response to changes in osmolality.Hyponatremia and hypo-osmolality lead to acute edema of the brain cells. The rigid calvaria prevent expansion ofbrain volume beyond a certain point, after which the brain cells must adapt to persistent hypo-osmolality. However,a rapid increase in brain water content of more than 5-10% leads to severe cerebral edema and herniation and isfatal.

In response to a decrease in osmolality, brain ECF fluid moves into the CSF. The brain cells then lose potassiumand intracellular organic osmolytes (amino acids, such as glutamate, glutamine, taurine, polyhydric alcohol,

myoinositol, methylamine, and creatinine). This occurs concurrently to prevent excessive brain swelling.[4]

Following correction of hyponatremia, the adaptive process does not match the extrusion kinetics. Electrolytesrapidly reaccumulate in the brain ECF within 24 hours, resulting in a significant overshoot above normal braincontents within the first 48 hours after correction. Organic osmolytes return to normal brain content very slowlyover 5-7 days. Electrolyte brain content returns to normal levels by the fifth day after correction, when organicosmolytes return to normal.



Irreversible neurologic damage and death may occur when the rate of correction of Na+ exceeds 0.5 mEq/L/h forpatients with severe hyponatremia. At this rate of correction, osmolytes that have been lost in defense againstbrain edema during the development of hyponatremia cannot be restored as rapidly when hyponatremia is rapidlycorrected. The brain cells are thus subject to osmotic injury, a condition termed osmotic demyelination. Certainfactors such as hypokalemia, severe malnutrition, and advanced liver disease predispose patients to this

devastating complication.[4]

Etiology

SIADH is most often caused by either inappropriate hypersecretion of ADH from its normal hypothalamic source orby ectopic production. The causes of SIADH can be divided into 4 broad categories: nervous system disorders,neoplasia, pulmonary diseases, and drug induced (which include those that [1] stimulate AVP release, [2]potentiate effects of AVP action, or [3] have an uncertain mechanism).

Nervous system disorders are as follows:

Acute psychosisAcute intermittent porphyriaBrain abscessCavernous sinus thrombosisCerebellar and cerebral atrophyCerebrovascular accidentCNS lupusDelirium tremensEncephalitis (viral or bacterial)EpilepsyGuillain-Barr syndromeHead traumaHerpes zoster (chest wall)HydrocephalusHypoxic ischemic encephalopathyMeningitis (viral, bacterial, tuberculous, and fungal)Midfacial hypoplasiaMultiple sclerosisPerinatal hypoxiaRocky Mountain spotted feverSchizophreniaShy-Drager syndromeSubarachnoid hemorrhageSubdural hematomaVentriculoatrial shunt obstructionWernicke encephalopathy

Neoplasia disorders are as follows:

Pulmonary - Lung carcinoma and mesotheliomaGastrointestinal - Carcinomas of the duodenum, pancreas, and colonGenitourinary - Adrenocortical carcinoma; carcinomas of cervix, ureter/bladder, and prostate; and ovariantumorsOther - Brain tumors, carcinoid tumors, Ewing sarcoma, leukemia, lymphoma, nasopharyngeal carcinoma,neuroblastoma (olfactory), and thymoma

Pulmonary disorders are as follows:

Acute bronchitis/bronchiolitisAcute respiratory failureAspergillosis (cavitary lesions)



AsthmaAtelectasisBacterial pneumoniaChronic obstructive lung diseaseCystic fibrosisEmphysemaEmpyemaPneumonia (viral, bacterial [mycoplasmal], fungal)PneumothoraxPositive pressure ventilationPulmonary abscessPulmonary fibrosisSarcoidosisTuberculosisViral pneumonia

Drugs that stimulate AVP release are as follows:

AcetylcholineAntineoplastic agents - Adenine arabinoside, cyclophosphamide, ifosfamide, vincristine, vinblastineBarbituratesBromocriptineCarbacholChlorpropamideClofibrateCyclopropaneDibenzazepines (eg, carbamazepine, oxcarbazepineHalothaneHaloperidolHistamineIsoproterenolLorcainideOpiates e.g. MorphineNicotine (inhaled tobacco)Nitrous oxidePhenothiazines (eg, thioridazine)ThiopentalMAOIs (eg, tranylcypromine)Tricyclic antidepressants (eg, amitriptyline, desipramine)

Drugs that potentiate the effects of AVP action (primarily facilitates peripheral action of ADH) are as follows:

ClofibrateGriseofulvinHypoglycemic agents Metformin, phenformin, tolbutamideOxytocin (large doses)Prostaglandin synthetase inhibitors (inhibit renal PGE2 synthesis) Indomethacin, aspirin, nonsteroidal

anti-inflammatory drugsTheophyllineTriiodothyronineVasopressin analogs (eg, AVP, DDAVP)

Drugs with an uncertain mechanism are as follows:

Antineoplastic agents Cisplatin, melphalan, methotrexate, imatinibCiprofloxacinClomipramineEcstasy



Phenoxybenzamine

Na+ valproateSSRIs (eg, sertraline, fluoxetine, paroxetine)Thiothixene

The list of drugs that can induce SIADH is long. SIADH has been reported as an adverse effect of multiple

psychotropic medications.[5] Many chemotherapeutic drugs cause nausea, which is a powerful stimulus ofvasopressin secretion. SIADH is also a leading cause of hyponatremia in children following chemotherapy or stemcell transplantation.

Miscellaneous causes are as follows:

Exercise-induced hyponatremiaGiant cell arteritisHIV infection - Hyponatremia has been reported in as many as 40% of adult patients with HIV infection.Patients with acquired immunodeficiency syndrome (AIDS) can have many potential causes for increased

ADH secretion, including volume depletion and infection of the lungs and the CNS.[6] Although one third ofthe hyponatremic patients with AIDS are clinically hypovolemic, the remaining hyponatremic patients fulfillmost of the criteria for SIADH.Idiopathic

Epidemiology

Occurrence in the United States

Hyponatremia is the most common electrolyte derangement occurring in hospitalized patients. When defined as

plasma Na+ concentration of less than 135 mEq/L, the prevalence of hyponatremia in hospitalized patients has

been reported in different studies as being between 2.5% and 30%.[7, 8, 9, 10] In the majority of cases, thehyponatremia was hospital acquired or aggravated by the hospitalization and may be secondary to the

administration of hypotonic intravenous (IV) fluids.[7] SIADH can also arise postoperatively from stress, pain, andmedications used. However, not all hospital-acquired hyponatremia is SIADH and SIADH should be differentiatedfrom the hyponatremia that occurs in patients with limited capacity to excrete free water, such as in patients withchronic kidney disease.

Sex- and age-related demographics

Increasing age (>30 y) is a risk factor for hyponatremia in hospitalized patients.[10] Men appear to be more likely to

develop mild or moderate, but not severe, hyponatremia.[10] Low body weight is also a risk factor for hyponatremia.Women appear to be more prone to drug-induced hyponatremia and to exercise-induced hyponatremia (marathon

runners), although this may be an association with low body weight rather than sex.[3]

Prognosis

The prognosis of SIADH correlates with the underlying cause and to the effects of severe hyponatremia and itsoverzealous correction. Rapid and complete recovery tends to be the rule with drug-induced SIADH when theoffending agent is withdrawn. Successful treatment of pulmonary or CNS infection also can lead to correction ofSIADH. However, patients who present with neurologic symptoms or have severe hyponatremia even without

symptoms may develop permanent neurologic impairment. Patients whose serum Na+ is rapidly corrected,especially those who are asymptomatic, can also develop permanent neurologic impairment from central pontinemyelinolysis (CPM).

Complications

The following complications are noted in SIADH:

Cerebral edema may be observed when plasma osmolality decreases faster than 10 mOsm/kg/h. This can



lead to cerebral herniation.

Noncardiogenic pulmonary edema may develop, especially in marathon runners.[11]

CPM is the feared complication of excessive, overly rapid correction of hyponatremia. Typical features aredisorders of upper motor neurons, including spastic quadriparesis and pseudobulbar palsy, as well as

mental disorders ranging from confusion to coma.[12] The risk is increased in persons with hepatic failure,

potassium depletion, large burns, and malnutrition.[13] Premenopausal patients undergoing surgery,especially gynecologic or related procedures, and those with serum Na of less than 105 may also have anincreased risk. Once CPM occurs as a complication, there is no proven treatment.

Morbidity and mortality

Previously, mild hyponatremia was considered relatively asymptomatic. However, evidence suggests that evenmild hyponatremia can cause significant impairment, such as unsteady gait, and lead to frequent falls. This effect

may be greater in elderly persons, who are more sensitive to changes in serum Na+.[14]

The mortality of patients with hyponatremia (Na+ < 130 mEq/L) is increased 60-fold compared with that of patientswithout documented hyponatremia, although this may be partly related to their comorbid conditions rather than tothe hyponatremia itself. Predictors for higher morbidity and mortality rates include being hospitalized, acute onset,

and severity of hyponatremia.[9] When the Na+ concentration drops below 105 mEq/L, life-threatening

complications are much more likely to occur.[13]

In a retrospective case note review by Clayton and colleagues, patients with a multifactorial cause for

hyponatremia in an inpatient setting had significantly higher mortality rates.[15] The etiology of hyponatremia was a

more important prognostic indicator than the level of absolute serum Na+ in the patients. The outcome was leastfavorable in patients who were normonatremic at admission and became hyponatremic during the course of theirhospitalization.

Contributor Information and DisclosuresAuthorChristie P Thomas, MBBS, FRCP, FASN, FAHA Professor, Department of Internal Medicine, Division ofNephrology, Departments of Pediatrics and Obstetrics and Gynecology, Medical Director, Kidney andKidney/Pancreas Transplant Program, University of Iowa Hospitals and Clinics

Christie P Thomas, MBBS, FRCP, FASN, FAHA is a member of the following medical societies: AmericanCollege of Physicians, American Heart Association, American Society of Nephrology, and Royal College ofPhysicians

Disclosure: Nothing to disclose.

Coauthor(s)Mony Fraer, MD, FACP, FASN Assistant Professor, Division of Nephrology, Department of Medicine,University of Iowa Hospitals and Clinics; Staff Physician, Iowa City Veterans Affairs Medical Center


Chief EditorVecihi Batuman, MD, FACP, FASN Professor of Medicine, Section of Nephrology-Hypertension, TulaneUniversity School of Medicine; Chief, Medicine Service, Southeast Louisiana Veterans Health Care System

Vecihi Batuman, MD, FACP, FASN is a member of the following medical societies: American College ofPhysicians, American Society of Hypertension, American Society of Nephrology, and International Society ofNephrology


Additional Contributors



Howard A Bessen, MD Professor of Medicine, Department of Emergency Medicine, UCLA School of Medicine;Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of EmergencyPhysicians


Keenan Bora, MD Fellow, Medical Toxicology, Detroit Medical Center; Attending Physician, Medical CenterEmergency Services, Detroit

Keenan Bora, MD is a member of the following medical societies: American Academy of Clinical Toxicology,American Academy of Emergency Medicine, American College of Emergency Physicians, American College ofMedical Toxicology, and American Medical Association


Meher Chaudhry, MD Chief Resident, Department of Emergency Medicine, Detroit Receiving Hospital,University Health Center


Sonali Deshmukh, MBBS Consulting Staff, Omaha Nephrology, Nebraska

Sonali Deshmukh, MBBS is a member of the following medical societies: American Society of Nephrology


R obert J Ferry Jr, MD Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children'sHospital; Professor, Department of Pediatrics, University of Tennessee Health Science Center at Memphis; St.Jude Children's Research Hospital, Memphis, TN; Brigade Surgeon, 36th Sustainment Brigade, U.S. Army;Adjunct Professor, Pediatric Surgery Department, King Saud University, Riyadh, Saudi Arabia

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics,American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins PediatricEndocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers BureauHonoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Investigator; MacroGenics, Inc.Grant/research funds Investigator; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Investigator;NovoNordisk SA Grant/research funds Investigator; Diamyd Investigator

Stephen Kemp, MD, PhD Professor, Department of Pediatrics, Section of Pediatric Endocrinology, Universityof Arkansas College of Medicine and Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics,American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi BetaKappa, Southern Medical Association, and Southern Society for Pediatric Research


Eleanor Lederer, MD Professor of Medicine, Chief, Nephrology Division, Director, Nephrology TrainingProgram, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine;Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD is a member of the following medical societies: American Association for theAdvancement of Science, American Federation for Medical Research, American Society for Biochemistry andMolecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology,American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association,National Kidney Foundation, and Phi Beta Kappa

Disclosure: Dept of Veterans Affairs Grant/research funds Research



Syndrome of Inappropriate AntidiureticHormone Secretion

Author: Christie P Thomas, MBBS, FRCP, FASN, FAHA; Chief Editor: VecihiBatuman, MD, FACP, FASN more...

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; AssociateProfessor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, AmericanAcademy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society,Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research fundsPI; NovoNordisk Grant/research funds PI

Chike Magnus Nzerue, MD Associate Dean for Clinical Affairs, Vice-Chairman of Internal Medicine, MeharryMedical College

Chike Magnus Nzerue, MD is a member of the following medical societies: American Association for theAdvancement of Science, American College of Physicians, American College of Physicians-American Societyof Internal Medicine, American Society of Nephrology, and National Kidney Foundation


Jose F Pascual-y-Baralt, MD Chief, Division of Pediatric Nephrology, San Antonio Military Pediatric Center;Clinical Professor, Department of Pediatrics, University of Texas Health Science Campus

Jose F Pascual-y-Baralt, MD is a member of the following medical societies: American Academy of Pediatrics,American Society of Nephrology, American Society of Pediatric Nephrology, Association of Military Surgeons ofthe US, and International Society of Nephrology


Alexandr Rafailov, MD Staff Physician, Department of Emergency Medicine, State University of New YorkDownstate/Kings County Hospital


Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University ofFlorida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics,American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society,Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research


Erik D Schraga, MD Consulting Staff, Department of Emergency Medicine, Mills-Peninsula EmergencyMedical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara MedicalCenter


Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine,Research Director, State University of New York College of Medicine; Consulting Staff, Department ofEmergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians andSociety for Academic Emergency Medicine


Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical CenterCollege of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment



Updated: Feb 25, 2013Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College ofPharmacy; Pharmacy Editor, Medscape


Additional ContributorsHoward A Bessen, MD Professor of Medicine, Department of Emergency Medicine, UCLA School of Medicine;Program Director, Harbor-UCLA Medical Center

Howard A Bessen, MD is a member of the following medical societies: American College of EmergencyPhysicians


Keenan Bora, MD Fellow, Medical Toxicology, Detroit Medical Center; Attending Physician, Medical CenterEmergency Services, Detroit

Keenan Bora, MD is a member of the following medical societies: American Academy of Clinical Toxicology,American Academy of Emergency Medicine, American College of Emergency Physicians, American College ofMedical Toxicology, and American Medical Association


Meher Chaudhry, MD Chief Resident, Department of Emergency Medicine, Detroit Receiving Hospital,University Health Center


Sonali Deshmukh, MBBS Consulting Staff, Omaha Nephrology, Nebraska

Sonali Deshmukh, MBBS is a member of the following medical societies: American Society of Nephrology


R obert J Ferry Jr, MD Chief, Division of Pediatric Endocrinology and Metabolism, Le Bonheur Children'sHospital; Professor, Department of Pediatrics, University of Tennessee Health Science Center at Memphis; St.Jude Children's Research Hospital, Memphis, TN; Brigade Surgeon, 36th Sustainment Brigade, U.S. Army;Adjunct Professor, Pediatric Surgery Department, King Saud University, Riyadh, Saudi Arabia

Robert J Ferry Jr, MD is a member of the following medical societies: American Academy of Pediatrics,American Diabetes Association, American Medical Association, Endocrine Society, Lawson-Wilkins PediatricEndocrine Society, Society for Pediatric Research, and Texas Pediatric Society

Disclosure: Nutropin Speakers Bureau Honoraria Speaking and teaching; Genotropin Speakers BureauHonoraria Speaking and teaching; Eli Lilly & Co. Grant/research funds Investigator; MacroGenics, Inc.Grant/research funds Investigator; Ipsen, S.A. (formerly Tercica, Inc.) Grant/research funds Investigator;NovoNordisk SA Grant/research funds Investigator; Diamyd Investigator

Stephen Kemp, MD, PhD Professor, Department of Pediatrics, Section of Pediatric Endocrinology, Universityof Arkansas College of Medicine and Arkansas Children's Hospital

Stephen Kemp, MD, PhD is a member of the following medical societies: American Academy of Pediatrics,American Association of Clinical Endocrinologists, American Pediatric Society, Endocrine Society, Phi BetaKappa, Southern Medical Association, and Southern Society for Pediatric Research


Eleanor Lederer, MD Professor of Medicine, Chief, Nephrology Division, Director, Nephrology TrainingProgram, Director, Metabolic Stone Clinic, Kidney Disease Program, University of Louisville School of Medicine;Consulting Staff, Louisville Veterans Affairs Hospital

Eleanor Lederer, MD is a member of the following medical societies: American Association for the



Advancement of Science, American Federation for Medical Research, American Society for Biochemistry andMolecular Biology, American Society for Bone and Mineral Research, American Society of Nephrology,American Society of Transplantation, International Society of Nephrology, Kentucky Medical Association,National Kidney Foundation, and Phi Beta Kappa

Disclosure: Dept of Veterans Affairs Grant/research funds Research

Lynne Lipton Levitsky, MD Chief, Pediatric Endocrine Unit, Massachusetts General Hospital; AssociateProfessor of Pediatrics, Harvard Medical School

Lynne Lipton Levitsky, MD is a member of the following medical societies: Alpha Omega Alpha, AmericanAcademy of Pediatrics, American Diabetes Association, American Pediatric Society, Endocrine Society,Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research

Disclosure: Pfizer Grant/research funds P.I.; Tercica Grant/research funds Other; Eli Lily Grant/research fundsPI; NovoNordisk Grant/research funds PI

Chike Magnus Nzerue, MD Associate Dean for Clinical Affairs, Vice-Chairman of Internal Medicine, MeharryMedical College

Chike Magnus Nzerue, MD is a member of the following medical societies: American Association for theAdvancement of Science, American College of Physicians, American College of Physicians-American Societyof Internal Medicine, American Society of Nephrology, and National Kidney Foundation


Jose F Pascual-y-Baralt, MD Chief, Division of Pediatric Nephrology, San Antonio Military Pediatric Center;Clinical Professor, Department of Pediatrics, University of Texas Health Science Campus

Jose F Pascual-y-Baralt, MD is a member of the following medical societies: American Academy of Pediatrics,American Society of Nephrology, American Society of Pediatric Nephrology, Association of Military Surgeons ofthe US, and International Society of Nephrology


Alexandr Rafailov, MD Staff Physician, Department of Emergency Medicine, State University of New YorkDownstate/Kings County Hospital


Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University ofFlorida; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics,American College of Epidemiology, American Pediatric Society, Endocrine Society, Florida Pediatric Society,Lawson-Wilkins Pediatric Endocrine Society, and Society for Pediatric Research


Erik D Schraga, MD Consulting Staff, Department of Emergency Medicine, Mills-Peninsula EmergencyMedical Associates; Consulting Staff, Permanente Medical Group, Kaiser Permanente, Santa Clara MedicalCenter


Richard H Sinert, DO Associate Professor of Emergency Medicine, Clinical Assistant Professor of Medicine,Research Director, State University of New York College of Medicine; Consulting Staff, Department ofEmergency Medicine, Kings County Hospital Center

Richard H Sinert, DO is a member of the following medical societies: American College of Physicians andSociety for Academic Emergency Medicine




Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical CenterCollege of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College ofPharmacy; Pharmacy Editor, Medscape


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syndrome of inappropriate antidiuretic hormone secretion siadh

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